Macrophages and dendritic cells which are cells taking charge of the innate immunity express receptors (pattern-recognition receptors: PRRs) for recognizing specific molecular patterns (pathogen-associated molecular patterns: PAMPs) present on pathogenic microbes invading an organism.
One of PRRs playing the most important role for macrophages and dendritic cells to recognize foreign microbes is a Toll-like receptor (TLR). At present, 13 types of TLRs have been identified in mammals. It is known that most of these TLRs mainly recognize PAMPs of bacteria. After a TLR recognizes PAMPs, TIR (Toll/IL-1 receptor) in a cytoplasm sends a signal, and finally activation of NF-κB and MAPK (mitogen-activated protein kinase) is induced.
In macrophages and dendritic cells, the activation of NF-κB, MAPK, and the like induces production of inflammatory cytokines such as TNF-α (tumor necrosis factor-α), IL (interleukin)-6, and IL-12, and is involved in suppression of infection expansion and determination of differentiation for T cells. Moreover, a dendritic cell matured by TLR signaling presents the antigen to a lymphocyte such as a B cell and a T cell, and induces proliferation of the antigen-specific lymphocyte. In this manner, TLRs play an important role not only in the innate immune system but also in the adaptive immune system.
Recently, immunostimulatory substances have been developed utilizing TLR signaling. For example, Patent Literature 1 discloses a technique for the purpose of immunostimulation by TLR signaling: an immunostimulatory composition comprising an isolated RNA oligomer 5 to 40 nucleotides long having a base sequence comprising at least one guanine and at least one uracil, and optionally a cationic lipid. Moreover, it is described that an isolated RNA oligomer produced by a nucleic acid synthesis method is preferably used as a nucleic acid serving as an effective component of the immunostimulatory composition (Paragraph 73 in the specification). Nevertheless, the literature does not disclose a result of an experiment conducted in a living organism, a so-called in vivo experiment. Accordingly, it is not certain whether such a synthetic RNA oligomer actually demonstrates a safe immunostimulating action in a living organism. In addition, the literature does not specifically disclose at all to what degree such a synthetic RNA oligomer demonstrates an effective immunostimulating effect in a living organism.
Further, Patent Literature 2 discloses a technique: an oligodeoxynucleotide having an immunostimulating action, and comprising a certain specific base sequence. Nevertheless, Patent Literature 2 merely discloses the result of examining a mitogen activity, in other words, cell division promoting activity, in the genomic DNA of a bacterium belonging to the genus Bifidobacterium in Example, and does not disclose at all a direct experimental result for whether an immunostimulating action exists or not.
Meanwhile, studies have reported so far that the health effects of lactic acid bacteria include actions for intestinal function regulation, cancer risk reduction, prevention of atopic dermatitis, allergy reduction, biological defense mechanism, blood cholesterol reduction, blood pressure reduction, and so forth (Non Patent Literatures 1 to 5). Moreover, lactic acid bacteria taken orally are incorporated in the intestinal tract from the Peyer's patch (PP) and phagocytized by macrophages, dendritic cells, and the like located in the PP. This is believed to activate the immune cells, stimulating innate immunity. Furthermore, it has been reported that lactic acid bacteria are recognized by TLR (Non Patent Literature 6). It is believed that lactic acid bacteria modulate the function of macrophages and dendritic cells through TLR signaling. Thus, identification of the effective component of lactic acid bacteria leads to development of drugs for modulating specific cytokine production, and can be utilized in the medical field, as well. Nevertheless, the detail of the substance which may serve as the main source of an immunomodulation action and a cytokine production-modulating-action of lactic acid bacteria has not been revealed yet.